A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis.

Rikin K Shah, Mary Munson, Klaas J Wierenga, Hanumantha R Pokala, Peter E Newburger, David Crawford

Pediatric blood & cancer 2017 Sep

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VPS45-associated severe congenital neutropenia (SCN) is a rare disorder characterized by life-threating infections, neutropenia, neutrophil and platelet dysfunction, poor response to filgrastim, and myelofibrosis with extramedullary hematopoiesis. We present a patient with SCN due to a homozygous c.1403C>T (p.P468L) mutation in VPS45, critical regulator of SNARE-dependent membrane fusion. Structural modeling indicates that P468, like the T224 and E238 residues affected by previously reported mutations, cluster in a VPS45 "hinge" region, indicating its critical role in membrane fusion and VPS45-associated SCN. Bone marrow transplantation, complicated by early graft failure rescued with stem cell boost, led to resolution of the hematopoietic phenotype. © 2017 Wiley Periodicals, Inc.

Citation

Rikin K Shah, Mary Munson, Klaas J Wierenga, Hanumantha R Pokala, Peter E Newburger, David Crawford. A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis. Pediatric blood & cancer. 2017 Sep;64(9)